Disruption of Lipid Metabolism Genes Causes Tissue Overgrowth Associated with Altered Developmental Signaling

English version České info

Developmental patterning requires the precise interplay of numerous intercellular signaling pathways to ensure that cells are properly specified during tissue formation and organogenesis. The spatiotemporal function of many developmental pathways is strongly influenced by the biosynthesis and intracellular trafficking of signaling components. Receptors and ligands must be trafficked to the cell surface where they interact, and their subsequent endocytic internalization and endosomal trafficking is critical for both signal propagation and its down-modulation. In a forward genetic screen for mutations that alter intracellular Notch receptor trafficking in Drosophila melanogaster, we recovered mutants that disrupt genes encoding serine palmitoyltransferase and acetyl-CoA carboxylase. Both mutants cause Notch, Wingless, the Epidermal Growth Factor Receptor (EFGR), and Patched to accumulate abnormally in endosomal compartments. In mosaic animals, mutant tissues exhibit an unusual non-cell-autonomous effect whereby mutant cells are functionally rescued by secreted activities emanating from adjacent wildtype tissue. Strikingly, both mutants display prominent tissue overgrowth phenotypes that are partially attributable to altered Notch and Wnt signaling. Our analysis of the mutants demonstrates genetic links between abnormal lipid metabolism, perturbations in developmental signaling, and aberrant cell proliferation.

Vyšlo v časopise: Disruption of Lipid Metabolism Genes Causes Tissue Overgrowth Associated with Altered Developmental Signaling. PLoS Genet 9(11): e32767. doi:10.1371/journal.pgen.1003917
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003917

Souhrn

Zdroje

1. KopanR, IlaganMX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137: 216–233.

2. FortiniME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16: 633–647.

3. CleversH (2006) Wnt/β-catenin signaling in development and disease. Cell 127: 469–480.

4. GagliardiM, PiddiniE, VincentJP (2008) Endocytosis: a positive or a negative influence on Wnt signalling? Traffic 9: 1–9.

5. BraySJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7: 678–689.

6. KovallRA (2008) More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 27: 5099–5109.

7. YamamotoS, CharngWL, BellenHJ (2010) Endocytosis and intracellular trafficking of Notch and its ligands. Curr Top Dev Biol 92: 165–200.

8. SeugnetL, SimpsonP, HaenlinM (1997) Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev Biol 192: 585–598.

9. GordonWR, Vardar-UluD, HistenG, Sanchez-IrizarryC, AsterJC, et al. (2007) Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14: 295–300.

10. LuH, BilderD (2005) Endocytic control of epithelial polarity and proliferation in Drosophila. Nat Cell Biol 7: 1232–1239.

11. VaccariT, BilderD (2005) The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating Notch trafficking. Dev Cell 9: 687–698.

12. ThompsonBJ, MathieuJ, SungHH, LoeserE, RørthP, et al. (2005) Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev Cell 9: 711–720.

13. MobergKH, SchelbleS, BurdickSK, HariharanIK (2005) Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev Cell 9: 699–710.

14. HerzHM, ChenZ, ScherrH, LackeyM, BolducC, et al. (2006) vps25 mosaics display non-autonomous cell survival and overgrowth, and autonomous apoptosis. Development 133: 1871–1880.

15. WeberU, ErogluC, MlodzikM (2003) Phospholipid membrane composition affects EGF receptor and Notch signaling through effects on endocytosis during Drosophila development. Dev Cell 5: 559–570.

16. HamelS, FantiniJ, SchweisguthF (2010) Notch ligand activity is modulated by glycosphingolipid membrane composition in Drosophila melanogaster. J Cell Biol 188: 581–594.

17. BehrensJ, von KriesJP, KuhlM, BruhnL, WedlichD, et al. (1996) Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382: 638–642.

18. van de WeteringM, CavalloR, DooijesD, van BeestM, van EsJ, et al. (1997) Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88: 789–799.

19. WillertK, BrownJD, DanenbergE, DuncanAW, WeissmanIL, et al. (2003) Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423: 448–452.

20. ZhaiL, ChaturvediD, CumberledgeS (2004) Drosophila Wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires Porcupine. J Biol Chem 279: 33220–33227.

21. PepperlJ, ReimG, LüthiU, KaechA, HausmannG, et al. (2013) Sphingolipid depletion impairs endocytic traffic and inhibits Wingless signaling. Mech Dev 130: 493–505.

22. HanadaK (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 1632: 16–30.

23. PerryDK (2002) Serine palmitoyltransferase: role in apoptotic de novo ceramide synthesis and other stress responses. Biochim Biophys Acta 1585: 146–152.

24. LajoieP, NabiIR (2010) Lipid rafts, caveolae, and their endocytosis. Int Rev Cell Mol Biol 282: 135–163.

25. SillenceDJ (2007) New insights into glycosphingolipid functions–storage, lipid rafts, and translocators. Int Rev Cytol 262: 151–189.

26. HannunYA, ObeidLM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9: 139–150.

27. TongL (2005) Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci 62: 1784–1803.

28. WakilSJ, Abu-ElheigaLA (2009) Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 50 Suppl: S138–143.

29. XuT, HarrisonSD (1994) Mosaic analysis using FLP recombinase. Methods Cell Biol 44: 655–681.

30. AshburnerM, ThompsonP, RooteJ, LaskoPF, GrauY, et al. (1990) The genetics of a small autosomal region of Drosophila melanogaster containing the structural gene for alcohol dehydrogenase. VII. Characterization of the region around the snail and cactus loci. Genetics 126: 679–694.

31. TweedieS, AshburnerM, FallsK, LeylandP, McQuiltonP, et al. (2009) FlyBase: enhancing Drosophila Gene Ontology annotations. Nucleic Acids Res 37: D555–559.

32. Adachi-YamadaT, GotohT, SugimuraI, TatenoM, NishidaY, et al. (1999) De novo synthesis of sphingolipids is required for cell survival by down-regulating c-Jun N-terminal kinase in Drosophila imaginal discs. Mol Cell Biol 19: 7276–7286.

33. PerizG, FortiniME (1999) Ca2+-ATPase function is required for intracellular trafficking of the Notch receptor in Drosophila. EMBO J 18: 5983–5993.

34. ZhangJ, SchulzeKL, HiesingerPR, SuyamaK, WangS, et al. (2007) Thirty-one flavors of Drosophila rab proteins. Genetics 176: 1307–1322.

35. LloydTE, AtkinsonR, WuMN, ZhouY, PennettaG, et al. (2002) Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila. Cell 108: 261–269.

36. MorataG, RipollP (1975) Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev Biol 42: 211–221.

37. GoodeS, MelnickM, ChouTB, PerrimonN (1996) The neurogenic genes egghead and brainiac define a novel signaling pathway essential for epithelial morphogenesis during Drosophila oogenesis. Development 122: 3863–3879.

38. ZhangH, AbrahamN, KhanLA, HallDH, FlemingJT, et al. (2011) Apicobasal domain identities of expanding tubular membranes depend on glycosphingolipid biosynthesis. Nat Cell Biol 13: 1189–1201.

39. CousoJP, BishopSA, Martinez AriasA (1994) The Wingless signalling pathway and the patterning of the wing margin in Drosophila. Development 120: 621–636.

40. NeumannCJ, CohenSM (1996) A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing. Development 122: 3477–3485.

41. de CelisJF, BrayS (1997) Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124: 3241–3251.

42. KimJ, SebringA, EschJJ, KrausME, VorwerkK, et al. (1996) Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature 382: 133–138.

43. FurriolsM, BrayS (2001) A model Notch response element detects Suppressor of Hairless-dependent molecular switch. Curr Biol 11: 60–64.

44. HuY, FortiniME (2003) Different cofactor activities in gamma-secretase assembly: evidence for a Nicastrin-Aph-1 subcomplex. J Cell Biol 161: 685–690.

45. NoloR, AbbottLA, BellenHJ (2000) Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell 102: 349–362.

46. ZeccaM, BaslerK, StruhlG (1996) Direct and long-range action of a Wingless morphogen gradient. Cell 87: 833–844.

47. TanimotoH, ItohS, ten DijkeP, TabataT (2000) Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. Mol Cell 5: 59–71.

48. WuS, HuangJ, DongJ, PanD (2003) hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114: 445–456.

49. Van der HorstDJ, RoosendaalSD, RodenburgKW (2009) Circulatory lipid transport: lipoprotein assembly and function from an evolutionary perspective. Mol Cell Biochem 326: 105–119.

50. HojjatiMR, LiZ, JiangXC (2005) Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. Biochim Biophys Acta 1737: 44–51.

51. Abu-ElheigaL, MatzukMM, KordariP, OhW, ShaikenovT, et al. (2005) Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci U S A 102: 12011–12016.

52. ParvyJP, NapalL, RubinT, PoldevinM, PerrinL, et al. (2012) Drosophila melanogaster acetyl-CoA-carboxylase sustains a fatty acid-dependent remote signal to waterproof the respiratory system. PLoS Genet 8: e1002925.

53. PizetteS, RabouilleC, CohenSM, ThérondP (2009) Glycosphingolipids control the extracellular gradient of the Drosophila EGFR ligand Gurken. Development 136: 551–561.

54. HerranzH, MilanM (2008) Signalling molecules, growth regulators and cell cycle control in Drosophila. Cell Cycle 7: 3335–3337.

55. Muñoz DescalzoS, Martinez AriasA (2012) The structure of Wntch signalling and the resolution of transition states in development. Sem Cell Dev Biol 23: 443–449.

56. Baena-LopezLA, Franch-MarroX, VincentJP (2009) Wingless promotes proliferative growth in a gradient-independent manner. Sci Signal 2: ra60.

57. HerranzH, PerezL, MartinFA, MilanM (2008) A Wingless and Notch double-repression mechanism regulates G1-S transition in the Drosophila wing. EMBO J 27: 1633–1645.

58. GiraldezAJ, CohenSM (2003) Wingless and Notch signaling provide cell survival cues and control cell proliferation during wing development. Development 130: 6533–6543.

59. JohnstonLA, SandersAL (2003) Wingless promotes cell survival but constrains growth during Drosophila wing development. Nat Cell Biol 5: 827–833.

60. PanákováD, SprongH, MaroisE, ThieleC, EatonS (2005) Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 435: 58–65.

61. DuboisL, LecourtoisM, AlexandreC, HirstE, VincentJP (2001) Regulated endocytic routing modulates Wingless signaling in Drosophila embryos. Cell 105: 613–624.

62. PiddiniE, MarshallF, DuboisL, HirstE, VincentJP (2005) Arrow (LRP6) and Frizzled2 cooperate to degrade Wingless in Drosophila imaginal discs. Development 132: 5479–5489.

63. SetoES, BellenHJ (2006) Internalization is required for proper Wingless signaling in Drosophila melanogaster. J Cell Biol 173: 95–106.

64. WilkinM, TongngokP, GenschN, ClemenceS, MotokiM, et al. (2008) Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of Notch in the endosomal trafficking pathway. Dev Cell 15: 762–772.

65. ZanolariB, FriantS, FunatoK, SutterlinC, StevensonBJ, et al. (2000) Sphingoid base synthesis requirement for endocytosis in Saccharomyces cerevisiae. EMBO J 19: 2824–2833.

66. ConibearE (2010) Converging views of endocytosis in yeast and mammals. Curr Opin Cell Biol 22: 513–518.

67. LingwoodD, SimonsK (2010) Lipid rafts as a membrane-organizing principle. Science 237: 46–50.

68. PontierSM, SchweisguthF (2012) Glycosphingolipids in signaling and development: from liposomes to model organisms. Dev Dyn 241: 92–106.

69. AcharyaJK, DasguptaU, RawatSS, YuanC, SanxaridisPD, et al. (2008) Cell-nonautonomous function of ceramidase in photoreceptor homeostasis. Neuron 57: 69–79.

70. SwinnenJV, BrusselmansK, VerhoevenG (2006) Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr Metab Care 9: 358–365.

71. SaddoughiSA, SongP, OgretmenB (2008) Roles of bioactive sphingolipids in cancer biology and therapeutics. Subcell Biochem 49: 413–440.

72. ChangHC, NewmyerSL, HullMJ, EbersoldM, SchmidSL, et al. (2002) Hsc70 is required for endocytosis and clathrin function in Drosophila. J Cell Biol 159: 477–487.

73. LaJeunesseDR, BucknerSM, LakeJ, NaC, PirtA, et al. (2004) Three new Drosophila markers of intracellular membranes. Biotechniques 36: 784–788, 790.

74. BobinnecY, MarcaillouC, MorinX, DebecA (2003) Dynamics of the endoplasmic reticulum during early development of Drosophila melanogaster. Cell Motil Cytoskeleton 54: 217–225.

75. PaiLM, OrsulicS, BejsovecA, PeiferM (1997) Negative regulation of Armadillo, a Wingless effector in Drosophila. Development 124: 2255–2266.

76. SatoA, KojimaT, Ui-TeiK, MiyataY, SaigoK (1999) Dfrizzled-3, a new Drosophila Wnt receptor, acting as an attenuator of Wingless signaling in wingless hypomorphic mutants. Development 126: 4421–4430.

77. RochF, SerrasF, CifuentesFJ, CorominasM, AlsinaB, et al. (1998) Screening of larval/pupal P-element induced lethals on the second chromosome in Drosophila melanogaster: clonal analysis and morphology of imaginal discs. Mol Gen Genet 257: 103–112.

78. FehonRG, KoohPJ, RebayI, ReganCL, XuT, et al. (1990) Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61: 523–534.

79. DiederichRJ, MatsunoK, HingH, Artavanis-TsakonasS (1994) Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. Development 120: 473–481.

80. QiH, RandMD, WuX, SestanN, WangW, et al. (1999) Processing of the Notch ligand Delta by the metalloprotease Kuzbanian. Science 283: 91–94.

81. BrookWJ, CohenSM (1996) Antagonistic interactions between Wingless and Decapentaplegic responsible for dorsal-ventral pattern in the Drosophila leg. Science 273: 1373–1377.

82. DuncanDM, BurgessEA, DuncanI (1998) Control of distal antennal identity and tarsal development in Drosophila by spineless-aristapedia, a homolog of the mammalian dioxin receptor. Genes Dev 12: 1290–1303.

83. PatelNH, Martin-BlancoE, ColemanKG, PooleSJ, EllisMC, et al. (1989) Expression of engrailed proteins in arthropods, annelids, and chordates. Cell 58: 955–968.

84. CrackD, SecombeJ, CoombeM, BrumbyA, SaintR, et al. (2002) Analysis of Drosophila Cyclin EI and II function during development: identification of an inhibitory zone within the morphogenetic furrow of the eye imaginal disc that blocks the function of Cyclin EI but not Cyclin EII. Dev Biol 241: 157–171.

85. KühnleinRP, FrommerG, FriedrichM, Gonzalez-GaitanM, WeberA, et al. (1994) spalt encodes an evolutionarily conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo. EMBO J 13: 168–179.

86. CoumailleauF, FürthauerM, KnoblichJA, González-GaitánM (2009) Directional Delta and Notch trafficking in Sara endosomes during asymmetric cell division. Nature 458: 1051–1055.

87. OdaH, UemuraT, HaradaY, IwaiY, TakeichiM (1994) A Drosophila homolog of Cadherin associated with Armadillo and essential for embryonic cell-cell adhesion. Dev Biol 165: 716–726.

88. ParnasD, HaghighiAP, FetterRD, KimSW, GoodmanCS (2001) Regulation of postsynaptic structure and protein localization by the Rho-type guanine nucleotide exchange factor dPix. Neuron 32: 415–424.

89. PeiferM, SweetonD, CaseyM, WieschausE (1994) wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo. Development 120: 369–380.

90. CapdevilaJ, ParienteF, SampedroJ, AlonsoJL, GuerreroI (1994) Subcellular localization of the segment polarity protein Patched suggests an interaction with the Wingless reception complex in Drosophila embryos. Development 120: 987–998.

91. MotznyCK, HolmgrenR (1995) The Drosophila Cubitus Interruptus protein and its role in the Wingless and Hedgehog signal transduction pathways. Mech Dev 52: 137–150.